The present disclosure relates generally to inhibitors of protein tyrosine phosphatases (PTPs). More particularly, the present disclosure relates to hydroxyindole carboxylic acid based inhibitors of oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2).
Protein tyrosine phosphatases (PTPs) play important roles in the regulation of numerous kinds of cellular processes, such as cell growth, proliferation, cellular differentiation and oncogenic transformation. The balance between dephosphorylation by protein tyrosine phosphatase (PTP) and phosphorylation by its counter-part, tyrosine kinase, is crucial for normal physiological function. PTPs are increasingly viewed as valuable drug targets. For example, the Src homology 2 (SH2)-domain containing protein tyrosine phosphatase-2 (SHP2), encoded by tyrosine-protein phosphatase non-receptor type 11 (PTPN11), is a non-receptor protein tyrosine phosphatase (PTP) containing two tandem Src homology-2 (SH2) domains. SHP2 is widely expressed in most tissues and plays a positive role in various signaling transduction pathways downstream of growth factor and cytokine receptors to regulate a diversity of cell functions. The catalytic activity of SHP2 is required for full activation of the Ras-ERK1/2 cascade that is mediated through SHP2-catalyzed dephosphorylation of substrates that are negatively regulated by tyrosine phosphorylation. SHP2 is recognized as a bona fide oncogene; gain-of-function SHP2 mutations leading to increased phosphatase activity-caused Noonan syndrome, as well as multiple forms of leukemia (e.g., juvenile myelomonocytic leukemia, acute myeloid leukemia, myelodysplastic syndrome, acute lymphoid leukemia) and various kinds of solid tumors (e.g., lung adenocarcinoma, colon cancer, neuroblastoma, glioblastoma, melanoma, hepatocellular carcinoma, and prostate cancer). Accordingly, SHP2 represents a promising target for multiple cancers (e.g., triple-negative and HER2+ breast cancer, cancers caused by abnormal activation of receptor protein tyrosine kinases (PTKs), some of which respond poorly to kinase inhibitor monotherapy) and draws increasing interest in the development of SHP2 inhibitors.
The highly positive and conserved charged PTP active site presents a tremendous challenge for the development of potent and selective PTP inhibitors bearing an optimal pharmacological property. Notably, it has been recognized that the binding affinity between pTyr and PTP active site is modest. Furthermore, with regard to PTP substrate recognition, both the pTyr and its flanking residues together make significant contributions. Therefore, a highly efficient strategy for PTP inhibitor discovery was proposed to bind both the active site and nearby non-conserved pocket with a linker to increase activity and selectivity. Large numbers of potent and selective PTP inhibitors have been reported using this strategy. Most of the PTP inhibitors reported are pTyr mimetics, which usually bear two or more acid groups. The poly negative charge properties of these previously produced inhibitors, however, result in these inhibitors lacking cell membrane permeability and are thus not drug-like.
Previously, hydroxyindole carboxylic acid was identified as a pTyr mimic. Moreover, the cellular effective inhibitor IIB08, the structure shown in FIG. 1 and having an IC50 of 5.5 μM for SHP2, was identified and determined to have 3-fold selectivity for SHP1 and PTP1B. Furthermore, IIB08 blocked growth factor stimulated ERK1/2 activation and hematopoietic progenitor proliferation. Encouragingly, treatment of leukemic mice with IIB08 and PI3Kinase inhibitor, LY294002, significantly prolonged the survival of mice compared to mice treated with either inhibitor alone in vivo. Despite the efficacious cellular activity and favorable in vivo anti-leukemia ability, the potency of IIB08 is still at greater than 1.0 μM level. Accordingly, there exists a need to develop improved hydroxyindole carboxylic acid compounds for inhibiting PTPs.